Browse > Article
http://dx.doi.org/10.5483/BMBRep.2017.50.6.059

Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2  

Kim, Myung-Jin (Department of Biological Sciences, Sookmyung Women's University)
Park, Seon Young (Department of Biological Sciences, Sookmyung Women's University)
Chang, Hae Ryung (Department of Biological Sciences, Sookmyung Women's University)
Jung, Eun Young (Department of Biological Sciences, Sookmyung Women's University)
Munkhjargal, Anudari (Department of Biological Sciences, Sookmyung Women's University)
Lim, Jong-Seok (Department of Biological Sciences, Sookmyung Women's University)
Lee, Myeong-Sok (Department of Biological Sciences, Sookmyung Women's University)
Kim, Yonghwan (Department of Biological Sciences, Sookmyung Women's University)
Publication Information
BMB Reports / v.50, no.6, 2017 , pp. 308-317 More about this Journal
Abstract
Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth $factor-{\beta}$ ($TGF-{\beta}$) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment.
Keywords
BMPR2; Embryogenesis; Mutation; Osteogenesis; Pathogenesis;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Nasim MT, Ghouri A, Patel B et al (2008) Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet 17, 1683-1694   DOI
2 Little SC and Mullins MC (2009) Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol 11, 637-643   DOI
3 Sun P, Wang J, Zheng Y, Fan Y and Gu Z (2012) BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer. Dent Mater J 31, 239-248   DOI
4 Knaus P and Sebald W (2001) Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily. Biol Chem 382, 1189-1195
5 Greenwald J, Groppe J, Gray P et al (2003) The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell 11, 605-617   DOI
6 Harper RL, Reynolds AM, Bonder CS and Reynolds PN (2016) BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology 21, 727-733   DOI
7 Zhang D, Mehler MF, Song Q and Kessler JA (1998) Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression. J Neurosci 18, 3314-3326   DOI
8 Franzen A, Piek E, Westermark B, ten Dijke P and Heldin NE (1999) Expression of transforming growth factor-beta1, activin A, and their receptors in thyroid follicle cells: negative regulation of thyrocyte growth and function. Endocrinology 140, 4300-4310   DOI
9 Rege J, Nishimoto HK, Nishimoto K, Rodgers RJ, Auchus RJ and Rainey WE (2015) Bone Morphogenetic Protein-4 (BMP4): A Paracrine Regulator of Human Adrenal C19 Steroid Synthesis. Endocrinology 156, 2530-2540   DOI
10 Wu X, Sagave J, Rutkovskiy A et al (2014) Expression of bone morphogenetic protein 4 and its receptors in the remodeling heart. Life Sci 97, 145-154   DOI
11 Bush KT, Sakurai H, Steer DL et al (2004) TGF-beta superfamily members modulate growth, branching, shaping, and patterning of the ureteric bud. Dev Biol 266, 285-298   DOI
12 Kang Q, Sun MH, Cheng H et al (2004) Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther 11, 1312-1320   DOI
13 Howe JR, Bair JL, Sayed MG et al (2001) Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28, 184-187   DOI
14 Kim IY, Lee DH, Lee DK et al (2004) Loss of expression of bone morphogenetic protein receptor type II in human prostate cancer cells. Oncogene 23, 7651-7659   DOI
15 Kodach LL, Wiercinska E, de Miranda NF et al (2008) The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology 134, 1332-1341   DOI
16 Schulz TJ and Tseng YH (2009) Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 20, 523-531   DOI
17 Mayeur C, Leyton PA, Kolodziej SA, Yu B and Bloch KD (2014) BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism. Blood 124, 2116-2123   DOI
18 Dichmann DS, Miller CP, Jensen J, Scott Heller R and Serup P (2003) Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas. Dev Dyn 226, 663-674   DOI
19 Razzouk S and Sarkis R (2012) BMP-2: biological challenges to its clinical use. N Y State Dent J 78, 37-39
20 Luu HH, Song WX, Luo X et al (2007) Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res 25, 665-677   DOI
21 Kanakaris NK and Giannoudis PV (2008) Clinical applications of bone morphogenetic proteins: current evidence. J Surg Orthop Adv 17, 133-146
22 Sun J, Li J, Li C and Yu Y (2015) Role of bone morphogenetic protein-2 in osteogenic differentiation of mesenchymal stem cells. Mol Med Rep 12, 4230-4237   DOI
23 Hyun SJ, Han DK, Choi SH et al (2005) Effect of recombinant human bone morphogenetic protein-2, -4, and -7 on bone formation in rat calvarial defects. J Periodontol 76, 1667-1674   DOI
24 King JA, Marker PC, Seung KJ and Kingsley DM (1994) BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol 166, 112-122   DOI
25 Pi CJ, Liang KL, Ke ZY et al (2016) Adenovirus-mediated expression of vascular endothelial growth factor-a potentiates bone morphogenetic protein9-induced osteogenic differentiation and bone formation. Biol Chem 397, 765-775
26 Daluiski A, Engstrand T, Bahamonde ME et al (2001) Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27, 84-88
27 Hogan BL (1996) Bone morphogenetic proteins in development. Curr Opin Genet Dev 6, 432-438   DOI
28 Zhao GQ (2003) Consequences of knocking out BMP signaling in the mouse. Genesis 35, 43-56   DOI
29 Nohe A, Hassel S, Ehrlich M et al (2002) The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277, 5330-5338   DOI
30 Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI and Knaus P (2000) Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11, 1023-1035   DOI
31 Wrana JL, Attisano L, Carcamo J et al (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003-1014   DOI
32 Koenig BB, Cook JS, Wolsing DH et al (1994) Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol 14, 5961-5974   DOI
33 Miyazono K, Maeda S and Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16, 251-263   DOI
34 Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P and Souchelnytskyi S (2004) Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 4, 1346-1358   DOI
35 Heldin CH and Moustakas A (2012) Role of Smads in TGFbeta signaling. Cell Tissue Res 347, 21-36   DOI
36 Murakami G, Watabe T, Takaoka K, Miyazono K and Imamura T (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14, 2809-2817   DOI
37 Zhu H, Kavsak P, Abdollah S, Wrana JL and Thomsen GH (1999) A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687-693   DOI
38 Heinecke K, Seher A, Schmitz W, Mueller TD, Sebald W and Nickel J (2009) Receptor oligomerization and beyond: a case study in bone morphogenetic proteins. BMC Biol 7, 59   DOI
39 Nagashima T, Li Q, Clementi C, Lydon JP, DeMayo FJ and Matzuk MM (2013) BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest 123, 2539-2550   DOI
40 Wiley DM and Jin SW (2011) Bone Morphogenetic Protein functions as a context-dependent angiogenic cue in vertebrates. Semin Cell Dev Biol 22, 1012-1018   DOI
41 Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3, 680-686   DOI
42 Kim RY, Robertson EJ and Solloway MJ (2001) Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Dev Biol 235, 449-466   DOI
43 Zhang H and Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977-2986
44 Winnier G, Blessing M, Labosky PA and Hogan BL (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev 9, 2105-2116   DOI
45 Jena N, Martin-Seisdedos C, McCue P and Croce CM (1997) BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. Exp Cell Res 230, 28-37   DOI
46 Tillet E and Bailly S (2014) Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet 5, 456
47 Rao SM, Ugale GM and Warad SB (2013) Bone morphogenetic proteins: periodontal regeneration. N Am J Med Sci 5, 161-168   DOI
48 Sieber C, Kopf J, Hiepen C and Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev 20, 343-355   DOI
49 Lin SJ, Lerch TF, Cook RW, Jardetzky TS and Woodruff TK (2006) The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding. Reproduction 132, 179-190   DOI
50 Ogata T, Wozney JM, Benezra R and Noda M (1993) Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells. Proc Natl Acad Sci U S A 90, 9219-9222   DOI
51 Ogata T and Noda M (1991) Expression of Id, a negative regulator of helix-loop-helix DNA binding proteins, is down-regulated at confluence and enhanced by dexamethasone in a mouse osteoblastic cell line, MC3T3E1. Biochem Biophys Res Commun 180, 1194-1199   DOI
52 Katagiri T, Imada M, Yanai T, Suda T, Takahashi N and Kamijo R (2002) Identification of a BMP-responsive element in Id1, the gene for inhibition of myogenesis. Genes Cells 7, 949-960   DOI
53 Ito Y and Miyazono K (2003) RUNX transcription factors as key targets of TGF-beta superfamily signaling. Curr Opin Genet Dev 13, 43-47   DOI
54 Maeda S, Hayashi M, Komiya S, Imamura T and Miyazono K (2004) Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. EMBO J 23, 552-563   DOI
55 Lee S, Cho HY, Bui HT and Kang D (2014) The osteogenic or adipogenic lineage commitment of human mesenchymal stem cells is determined by protein kinase C delta. BMC Cell Biol 15, 42   DOI
56 Satija NK, Gurudutta GU, Sharma S et al (2007) Mesenchymal stem cells: molecular targets for tissue engineering. Stem Cells Dev 16, 7-23   DOI
57 Beppu H, Kawabata M, Hamamoto T et al (2000) BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol 221, 249-258   DOI
58 Danesh SM, Villasenor A, Chong D, Soukup C and Cleaver O (2009) BMP and BMP receptor expression during murine organogenesis. Gene Expr Patterns 9, 255-265   DOI
59 Kim IY, Lee DH, Ahn HJ et al (2000) Expression of bone morphogenetic protein receptors type-IA, -IB and -II correlates with tumor grade in human prostate cancer tissues. Cancer Res 60, 2840-2844
60 Rigelsky CM, Jennings C, Lehtonen R, Minai OA, Eng C and Aldred MA (2008) BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. Am J Med Genet A 146A, 2551-2556   DOI
61 Park SW, Hur SY, Yoo NJ and Lee SH (2010) Somatic frameshift mutations of bone morphogenic protein receptor 2 gene in gastric and colorectal cancers with microsatellite instability. APMIS 118, 824-829   DOI
62 Schleinitz D, Kloting N, Bottcher Y et al (2011) Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity. PLoS One 6, e16155   DOI
63 Wu M, Chen G and Li YP (2016) TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res 4, 16009   DOI
64 Miyazono K, Kamiya Y and Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147, 35-51   DOI
65 Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67, 737-744   DOI
66 van Dinther M, Visser N, de Gorter DJ et al (2010) ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMPinduced osteoblast differentiation and bone formation. J Bone Miner Res 25, 1208-1215
67 Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR and Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci U S A 102, 5062-5067   DOI
68 Dyer LA, Pi X and Patterson C (2014) The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 25, 472-480   DOI
69 Amsalem AR, Marom B, Shapira KE et al (2016) Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor. Mol Biol Cell 27, 716-730   DOI
70 Lane KB, Machado RD, Pauciulo MW et al (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26, 81-84   DOI
71 Rosenzweig BL, Imamura T, Okadome T et al (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci U S A 92, 7632-7636   DOI
72 Sopory S, Nelsen SM, Degnin C, Wong C and Christian JL (2006) Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain. J Biol Chem 281, 34021-34031   DOI
73 Lee KM, Tsai KY, Wang N and Ingber DE (1998) Extracellular matrix and pulmonary hypertension: control of vascular smooth muscle cell contractility. Am J Physiol 274, H76-82
74 Atkinson C, Stewart S, Upton PD et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105, 1672-1678   DOI
75 Finkenzeller G, Hager S and Stark GB (2012) Effects of bone morphogenetic protein 2 on human umbilical vein endothelial cells. Microvasc Res 84, 81-85   DOI
76 Langenfeld EM and Langenfeld J (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2, 141-149
77 Wiley DM, Kim JD, Hao J, Hong CC, Bautch VL and Jin SW (2011) Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol 13, 686-692   DOI
78 de Jesus Perez VA, Alastalo TP, Wu JC et al (2009) Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol 184, 83-99   DOI
79 Takahashi H, Goto N, Kojima Y et al (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290, L450-458   DOI
80 Takahashi K, Kogaki S, Matsushita T, Nasuno S, Kurotobi S and Ozono K (2007) Hypoxia induces alteration of bone morphogenetic protein receptor signaling in pulmonary artery endothelial cell. Pediatr Res 61, 392-397   DOI
81 West J, Harral J, Lane K et al (2008) Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295, L744-755   DOI
82 Hee CK and Nicoll S (2006) Induction of osteoblast differentiation markers in human dermal fibroblasts: potential application to bone tissue engineering. Conf Proc IEEE Eng Med Biol Soc 1, 521-524
83 Onishi T, Ishidou Y, Nagamine T et al (1998) Distinct and overlapping patterns of localization of bone morphogenetic protein (BMP) family members and a BMP type II receptor during fracture healing in rats. Bone 22, 605-612   DOI
84 Lehnerdt G, Metz KA, Trellakis S, Jahnke K and Neumann A (2007) Signaling by way of type IB and II bone morphogenetic protein receptors regulates bone formation in otospongiosis. Laryngoscope 117, 812-816   DOI
85 Garimella R, Kacena MA, Tague SE, Wang J, Horowitz MC and Anderson HC (2007) Expression of bone morphogenetic proteins and their receptors in the bone marrow megakaryocytes of GATA-1(low) mice: a possible role in osteosclerosis. J Histochem Cytochem 55, 745-752   DOI
86 Yang C, Yang L, Wan M and Cao X (2010) Generation of a mouse model with expression of bone morphogenetic protein type II receptor lacking the cytoplasmic domain in osteoblasts. Ann N Y Acad Sci 1192, 286-291   DOI
87 Katagiri T, Yamaguchi A, Komaki M et al (1994) Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127, 1755-1766   DOI
88 Davis RL, Weintraub H and Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987-1000   DOI
89 Wright WE, Sassoon DA and Lin VK (1989) Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD. Cell 56, 607-617   DOI
90 Edmondson DG and Olson EN (1990) A gene with homology to the myc similarity region of MyoD1 is expressed during myogenesis and is sufficient to activate the muscle differentiation program. Genes Dev 4, 1450   DOI
91 Olson EN (1990) MyoD family: a paradigm for development? Genes Dev 4, 1454-1461   DOI
92 Yang J, Davies RJ, Southwood M et al (2008) Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension. Circ Res 102, 1212-1221   DOI
93 Katagiri T, Yamaguchi A, Ikeda T et al (1990) The nonosteogenic mouse pluripotent cell line, C3H10T1/2, is induced to differentiate into osteoblastic cells by recombinant human bone morphogenetic protein-2. Biochem Biophys Res Commun 172, 295-299   DOI
94 Wu N, Zhao Y, Yin Y, Zhang Y and Luo J (2010) Identification and analysis of type II TGF-beta receptors in BMP-9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. Acta Biochim Biophys Sin (Shanghai) 42, 699-708   DOI
95 Morrell NW (2010) Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. Adv Exp Med Biol 661, 251-264
96 Hamid R, Hedges LK, Austin E, Phillips JA 3rd, Loyd JE and Cogan JD (2010) Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. Clin Genet 77, 280-286   DOI
97 Ihida-Stansbury K, McKean DM, Lane KB et al (2006) Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 291, L694-702   DOI
98 Drake KM, Dunmore BJ, McNelly LN, Morrell NW and Aldred MA (2013) Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 49, 403-409   DOI